A Comparison of Clinical Practice Guidelines in the Initial Pharmacological Management of New-Onset Epilepsy in Adults

Transcription

1 FORMULARY MANAGEMENT A Comparison of Clinical Practice Guidelines in the Initial Pharmacological Management of New-Onset Epilepsy in Adults NALIN PAYAKACHAT, MS; KENT H. SUMMERS, RPh, PhD; and JOHN P. BARBUTO, MD ABSTRACT OBJECTIVE: Clinical practice guidelines (CPGs) are intended not only to provide supportive information for health care providers but also to act as a guide for health care policy decisions. However, extant CPGs do not always reach the same conclusions. The objective of this study was to compare recommendations for initial pharmacological treatment of new-onset epilepsy in adults as stated within published CPGs. METHODS: We performed a systematic review of CPGs, which were published by prominent national organizations between January 2000 and June 2005, regarding the initial pharmacological treatment of epilepsy in adults. RESULTS: Five CPGs and 1 evidence report were identified that focus on pharmaceutical management in epilepsy. The 3 guidelines most relevant to the question of new-onset epilepsy treatment in adults were developed by the American Academy of Neurology (AAN), Scottish Intercollegiate Guidelines Network (SIGN), and National Institute for Health and Clinical Excellence (NICE). AAN recommends the use of both recently introduced antiepileptic drugs (AEDs: gabapentin, lamotrigine, topiramate, and oxcarbazepine) and standard agents (carbamazepine, phenytoin, valproic acid/divalproex, and phenobarbital) in newly diagnosed epilepsy, i.e., a nontiered approach. Alternatively, NICE recommends using newer AEDs (lamotrigine, topiramate, and oxcarbazepine) only in patients who derive no benefit from older agents a tiered approach. SIGN notes that all AEDs licensed for monotherapy have similar efficacy in newly diagnosed epilepsy a recommendation for a nontiered approach. The newer AEDs (lamotrigine and oxcarbazepine) are recommended as first-line initial treatment as are standard agents (carbamazepine and valproic acid/divalproex). The NICE guideline includes economic and quality-of-life evidence in their recommendations while AAN and SIGN do not. In these regards, current data fails to show superiority for newer agents. CONCLUSION: In the past 5 years, several CPGs have been published in epilepsy management. Only 3 guidelines have explicit recommendations for initial pharmacological treatment of adults with epilepsy. With some variation regarding which medications are recommended from each group, all CPGs promote standard and newer AEDs as having similar clinical efficacy. Until efficacy, quality of life, or cost data for the newer agents demonstrates a superior outcome, older AEDs remain viable options as first-line for monotherapy in newly diagnosed patients and may provide cost benefits over newer agents. KEYWORDS: CPGs,, Epilepsy, Initial treatment, Policymakers, Policy J Manag Care Pharm. 2006;12(1):55-60 Authors NALIN PAYAKACHAT, MS, is a PhD student and KENT H. SUMMERS, RPh, PhD, is an associate professor; Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana; JOHN P. BARBUTO, MD, is director, Outpatient Neurology, HealthSouth Rehabilitation Hospital, Sandy, Utah. AUTHOR CORRESPONDENCE: Nalin Payakachat, MS, PhD Student, Department of Pharmacy Practice, School of Pharmacy and Pharmacal Sciences, Purdue University, R. Heine Pharmacy Building, Room 502, 575 Stadium Mall Dr., West Lafayette, IN 47907: Tel: (765) ; Fax: (765) ; npayakac@purdue.edu Copyright 2006, Academy of Managed Care Pharmacy. All rights reserved. Epilepsy is a life-altering chronic condition that affects approximately 2.3 million people in the United States, with 150,000 to 200,000 new cases diagnosed each year. 1 The annual cost of epilepsy is approximately $12.5 billion, with 85% of expenditures attributable to nonmedical costs such as lost productivity both at work and at home. 2 Patients with newly diagnosed epilepsy have approximately a 50% chance of seizure remission after initial treatment with moderate doses of antiepileptic drugs (AEDs). 3 The number of available AEDs has increased recently. Prior to 1990, carbamazepine, phenobarbital, phenytoin, primidone, valproic acid, and ethosuximide were used to treat all forms of epilepsy. Although these older AEDs are generally effective in newly diagnosed epilepsy and are much less expensive than newer agents, some undesirable characteristics such as complex pharmacokinetics and adverse-effect profiles make them less appealing to clinicians and patients. The newer U.S. Food and Drug Administration (FDA)-approved AEDs include felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide. It has been argued that the advantages of the newer agents compared with the older agents are fewer side effects and drug interactions. With the large number of AEDs available, physicians are presented with difficult drug selection decisions. While the most critical aspect of AED product selection is safety, tolerability, and efficacy, cost is an additional and increasingly important consideration. Concern about health care quality has contributed to policymakers need for the development of uniform and systematic guidelines to aid physicians in making better-informed decisions. 4 Clinical practice guidelines (CPGs) are systematically developed statements of clinical recommendations to assist practitioner and patient decisions regarding appropriate health care. Consistent use of CPGs promotes the concept of best practices in order to improve treatment outcomes. 5 CPGs rely on 2 basic assumptions: (1) outcomes identified in clinical trials are reproducible in normal practice and (2) adoption of effective treatment guidelines leads to improved treatment for the whole population. Guidelines developed by an evidence-based approach are founded upon conclusions supported by scientific evidence as well as expert opinion. Efforts are made to link the strength of recommendations to the quality of evidence. 4 In the past 5 years, several epilepsy management CPGs have been published that refer to efficacy and safety of both older and newer AEDs. This paper is intended to provide policymakers with a comparison of conclusions reached in the extant CPG s that deal with pharmacological choices for initial management Vol. 12, No. 1 January/February 2006 JMCP Journal of Managed Care Pharmacy 55

2 of epilepsy in adults. Specifically, we sought to answer the question How do current, prominent guidelines compare in regard to recommendations for treatment of new-onset epilepsy in adults? Thus, it does not address AED selection when treating refractory epilepsy, management of children, or any AED treatment patterns. It is intended to facilitate the practice of pharmacy benefit managers by providing information for policy-makers and to compare clinical treatment guidelines. Methods Search Strategy A systematic review process was applied to obtain relevant CPGs that were published by prominent national organizations between January 2000 and June 2005 in the United States and other countries (published in English only). We did not include the guidelines that were published before the year 2000 because we considered them to be outdated. 6,7 The research question in this review was What are the differences among guideline recommendations of new-onset seizure in adults? National CPGs were identified by a computerized search from various sources, including electronic databases, (e.g., MED- LINE, PsycINFO, Cochrane Library, Current Contents, and Proquest Research Library), guideline Web sites (e.g., the U.S. National Guideline Clearinghouse [NGC], National Institute for Health and Clinical Excellence [NICE], Scottish Intercollegiate Guidelines Network [SIGN], Agency for Healthcare Research and Quality [AHRQ]), and hand searches of relevant journals. MeSH terms used were epilepsy or seizure with limits of all adult: 19+ years, publication date from 2000/1/1 to 2005/6/31, English, practice guideline/ review, humans. Other key search terms were clinical practice guideline and epilepsy, antiepileptic drug and epilepsy, initial treatment and epilepsy, review and drug treatment of new-onset epilepsy in adult, monotherapy and newly diagnosed epilepsy, drug management and newly diagnosed epilepsy, first seizure, new-onset epilepsy, and first diagnosis. Inclusion and Exclusion Criteria Inclusion criteria regarding selection of CPGs were: (1) guidelines that are sponsored by governmental and prominent professional organizations, (2) publication in the English language, and (3) CPGs that address the role of AEDs in the initial management of epilepsy in adults (age >18 years). Exclusion criteria were: (1) CPGs in refractory epilepsy only, (2) CPGs of epilepsy treatment in childhood only, (3) any other examples of complex presentations of epilepsy that may be referred for specialist care, and (4) CPG does not address the research question How do current prominent guidelines compare in regard to recommendations for treatment of new onset epilepsy in adults? Searches of the reference lists and bibliographies of all papers for additional studies were performed as a part of the review. Comparison of Clinical Practice Guidelines Similarities and differences of the guidelines were evaluated and addressed to provide policymakers with information to support the use of CPGs in rational policymaking in the United States, focusing on the initial pharmacological treatment of new-onset epilepsy in adults. Results Five national CPGs and 1 evidence report were identified from a systematic search according to the inclusion criteria. These CPGs included 3 from the United Kingdom (NICE, National Collaborating Centre for Primary Care [NCCP], and Joint Epilepsy Council [JEC]), 1 from Scotland (SIGN) and 1 from the United States (American Academy of Neurology [AAN]) The evidence report was from AHRQ. 13 Characteristics of each are summarized in Table 1. Although some guidelines included some exclusionary criteria such as recommendations for refractory symptoms or children, they were included because they addressed the primary research question. AAN, in conjunction with the American Epilepsy Society, addressed specific initial drug agent selection in the first part of its guideline. 12 SIGN provided complete recommendations for epilepsy management for both adults and children. The NICE guideline reviewed all aspects of newer drugs for epilepsy in adults. The NCCP guideline regarding newly diagnosed patients mirrors the NICE guideline; therefore, it was excluded to prevent redundancy. We also excluded the JEC guideline and AHRQ report because they do not have specific therapeutic recommendations for initial treatment of epilepsy. After excluding the guidelines from NCCP, JEC, and AHRQ according to our established criteria, the CPGs from AAN, NICE, and SIGN were included in the final comparison chart (see Table 2). Discussion After comparing the guidelines, we found valid evidence that older, less-expensive AEDs still have an important role as firstline drugs of choice in adults with new-onset epilepsy; the role of newer AEDs is still controversial. SIGN and NICE guidelines contain recommendations to use AEDs as first-line treatment only under their licensed indications, while AAN recommendations include the use of AEDs that fall outside labeled FDA indications. 8,11,12,15 AAN and SIGN also recommend the use of newer agents as first-line treatment in newly diagnosed patients. SIGN states, Comparative, randomized, double-blind trials in patients with newly diagnosed partial and generalized tonicclonic seizures suggest similar efficacy for phenytoin, carbamazepine, sodium valproate, lamotrigine, and oxcarbazepine and The newer AEDs, lamotrigine and oxcarbazepine, seem to be better tolerated and may produce fewer long-term side effects and adverse interactions. 11 These recommendations are consistent with other scientific literature. 16 NICE supports the 56 Journal of Managed Care Pharmacy JMCP January/February 2006 Vol. 12, No. 1

3 Title TABLE 1 Objective Date of publication Type of document Intended users Type of patients Major outcomes consider Literature search dates Summary of National Practice Guidelines and Evidence Reports for Epilepsy Management (Published January 2000-June 2005) AHRQ 13 * Management of Newly Diagnosed Patients with Epilepsy: A Systematic Review of the Literature To systematically review the best available evidence in the published literature regarding health care services pertinent to the diagnosis, treatment, and monitoring of patients with a first diagnosis of epilepsy Sep Newly diagnosed (not specific in any age group) Health outcomes: clinical, HrQoL, and cost-effectiveness 1980-present AAN 12 Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new onset epilepsy To assess the evidence demonstrating efficacy, tolerability, and safety of 7 new AEDs (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies Apr Evidence report Developers of clinical Physicians practice guidelines and other qualityenhancement tools, those involved with reimbursement and coverage policies Children and adults with newly diagnosed partial and generalized epilepsies Efficacy, tolerability, and safety of newer AEDs Jan Sep and Sep May 2002 NICE 8 Newer drugs for epilepsy in adults To examine the clinical effectiveness, tolerability, and cost-effectiveness of gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and vigabatrin for epilepsy in adults Mar Adults with newly diagnosed or refractory epilepsy Clinical effectiveness; serious, rare, and long-term adverse events; costeffectiveness Inception-Sep NCCP 9 * The diagnosis and management of the epilepsies in adults and children in primary and secondary care To offer best-practice advice on the diagnosis, treatment, and management of the epilepsies in children and adults Oct Children, adolescents, adults, older people, women who are pregnant, women of childbearing potential, and people with learning disabilities All issues important in the diagnosis, treatment, and management of epilepsy in children and adults Evidence published up to the end of Dec JEC 10 * The JEC National Statement of Good Practice for the Treatment and Care of People Who Have Epilepsy To provide a series of recommendations for attaining high-quality National Health Service care for people with epilepsy in England Mar Patients, physicians, health care providers, care givers, those involved in public policy Individual health care professionals, people with epilepsy and their caregivers, health care commissioning organizations, Advanced-practice nurses, nurses, occupational therapists, physician assistants, physicians, psycholo- provider gists/ nonphysician, organizations behavioral health clinicians, social workers Individuals with epilepsy Rate of epilepsy misdiagnosis and efficacy of AEDs and their adverse-event profiles Not specific SIGN 11 Diagnosis and Management of Epilepsy in Adults A national clinical guideline To provide evidencebased recommendations on the diagnosis and treatment of epilepsy, including recommendations on AED treatment, management of drugresistant epilepsy, management of status epilepticus, management of provoked seizures, management of people with learning disability and epilepsy, and contraception, pregnancy, and menopause Apr (addendum released Jun. 7, 2004) Advanced practice nurses, patients, pharmacists, physician assistants, physicians, public health department social workers Adult patients with epilepsy or status epilepticus Clinical outcomes Method used * CPGs that were excluded from the final comparison. CPGs that were included in the final comparison (See Results section in article). AAN = American Academy of Neurology; AED = antiepileptic drug; AHRQ =Agency for Healthcare Research and Quality; CPG = clinical practice guideline; HrQoL = health-related quality of life; JEC = Joint Epilepsy Council; NCCP =National Collaborating Centre for Primary Care; NICE=National Institute for Health and Clinical Excellence; SIGN=Scottish Intercollegiate Guidelines Network. Vol. 12, No. 1 January/February 2006 JMCP Journal of Managed Care Pharmacy 57

4 TABLE 2 Guidelines Selected for Clinical Review Inclusion. Recommendations Regard the Initial Medication Choice With Typical Maintenance Dosing for Epilepsy in Adults AEDs as Monotherapy of Partial/Mix Generalized Typical Dose Cost/Month U.S.$ Tonic-Clonic Seizure AAN* NICE SIGN (mg)/day 14 Cost/Unit, U.S.$ (30-Day Supply) Phenobarbital 1st (97.2 mg) 2 Carbamazepine (generic Tegretol) 1st 1st 1st 1, (200 mg) 27 Tegretol XR 1.28 (400 mg XR tab) 96 Phenytoin (generic Dilantin) 1st 1st (100 mg cap) 28 Valproic acid (generic Depakene) 1st 1st 1st 1, (250 mg cap) 52 Ethosuximide (generic Zarontin) (250 mg) 47 Primidone (generic Mysoline) , (250 mg) 54 Gabapentin (generic Neurontin) 1st - - 1, (300 mg tab) 102 Divalproex (Depakote) 1st 1st 1st 1, (500 mg tab) 180 Divalproex (Depakote ER) 2.07 (500 mg ER tab) 187 Zonisamide (Zonegran) (100 mg) 123 Tiagabine (Gabitril) (16 mg) 208 Oxcarbazepine ( Trileptal) 1st 2nd 1st 1, (600 mg) 228 Topiramate (Topamax) 1st 2nd (200 mg) 236 Levetiracetam (Keppra) , (500 mg) 250 Lamotrigine (Lamictal) 1st 2nd 1st (200 mg) 287 * AAN: Patients with newly diagnosed epilepsy who require treatment can be initiated on standard AEDs such as carbamazepine, phenytoin, valproic acid, phenobarbital or on the new AEDs: lamotrigine, gabapentin, oxcarbazepine, or topiramate. Choice of AED will depend on individual patient characteristics. Both new and old drugs are 12 (p.1258) generally equally effective in new-onset epilepsy. The newer drugs tend to have fewer side effects. NICE: First-line monotherapy should be initiated with one of the older antiepileptic drugs such as carbamazepine or sodium valproate unless these drugs are not suitable because there are contraindications or the potential for interactions with other drugs the person is taking, because they have been poorly tolerated by the person in the past, 8 (section 4.3.2, p.22) or because the person is a woman of childbearing potential. The newer antiepileptic drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and vigabatrin within their licensed indications, are recommended for the management of epilepsy in people who have not benefited from treatment with the 8 (section 1.1, p.4) older antiepileptic drugs. SIGN: Carbamazepine, sodium valproate, lamotrigine, and oxcarbazepine can all be regarded as first-line treatments for partial and secondary generalized seizures. Sodium valproate and lamotrigine are drugs of choice for primary generalized seizures and should also be prescribed if there is any doubt about the seizure types and/or syndrome classification. The side-effect and interaction profiles should direct the choice of drug for the individual patient. All AEDs licensed for monotherapy have similar efficacy in newly diagnosed epilepsy. Note: Formulations of AEDs are not interchangeable and generic substitution should not be employed. All antiepileptic drugs licensed 11 (section 3.2, p.9) for monotherapy have similar efficacy in newly diagnosed epilepsy. Typical doses that were used in this table: (1) were the average typical full daily dose (neither starting nor maximum dose), (2) if used in combination with other AEDs, patient may require a different dose, and (3) are for comparison purpose only, not for specific treatment recommendation. 14 Prices were obtained from (accessed December 6, 2005). 1st=first-line drug; 2nd=second-line drug. AAN = American Academy of Neurology; AED = antiepileptic drug; ER =extended release; NICE=National Institute for Health and Clinical Excellence; SIGN=Scottish Intercollegiate Guidelines Network; XR=extended release. use of the older AEDs and clearly states that newer AEDs should be second-line in initial treatment, based upon a lack of goodquality evidence from clinical trials to support the preferential use of newer AED monotherapy over the older drugs. They state, Almost all studies comparing newer drugs with older drugs have found no statistically significant differences in terms of seizure-related outcomes. However, it cannot be concluded that the drugs have been shown to be equivalent in terms of efficacy. 8 One important clinical question for the treatment of newly diagnosed patients is whether lamotrigine, oxcarbazepine, and topiramate are more effective than older AEDs. This review found insufficient evidence from good-quality clinical trials to answer this question. 15 NICE suggests that a review of the adverse events and tolerability from clinical trials does not provide sufficiently consistent results necessary to draw conclusions to support a preference for the newer AEDs compared with the older ones. Important information uniquely found in NICE is the health-related quality-of-life (HrQoL) evidence review. Quality of life is an important advantage proposed for the newer AEDs. 58 Journal of Managed Care Pharmacy JMCP January/February 2006 Vol. 12, No. 1

5 NICE states, However, only nine of the 19 studies comparing monotherapy using newer drugs versus older drugs assessed quality-of-life and These studies do not provide strong evidence of improved quality of life with the newer drugs. 8 Based on a broader review of the literature, NICE concludes that there is insufficient evidence to confirm an advantage for the newer AEDs over the older agents related to their ability to improve patients HrQoL. AAN did mention in its guideline that the burden is on the treating physician to select the AED that is the most tolerable, has the lowest potential for harm, and has the least likelihood of negatively impacting quality of life ; however, AAN did not included this parameter in its review. The NICE guideline declares that the evidence on costeffectiveness considered by the reviewing committee indicates that none of the published economic evaluations satisfied the criteria for a robust economic evaluation, but monotherapy with the older AEDs is considerably less expensive, considering only drug cost. 15 They state, Even when the most optimistic treatment scenario for the newer drugs was compared with the worst-case treatment scenario for the older drugs, monotherapy with the older drugs was considerably less costly. 8 Finally, they conclude that the older monotherapies appeared to be cost effective when compared to newer AEDs for the treatment of newly diagnosed patients experiencing generalised seizures. 15 When comparing U.S. and European studies, a limiting factor is the insufficient cost-effectiveness and HrQoL information for AEDs used as initial treatment of epilepsy in the United States. AAN states, The older AEDs have an advantage of broad familiarity, lower cost, known efficacy, wide availability via coverage by third-party payers, and long-term experience and The new drugs are all substantially more expensive than the old. There is no literature that addresses the cost-benefit related to these issues. 12 In the United Kingdom, NICE asks pharmaceutical companies to submit both published and unpublished information to incorporate into the CPG. 15 This provides a broader foundation for the examination of cost-effectiveness and HrQoL assessments. Although the AHRQ guideline includes costs and HrQoL in its review, it does not have recommendations regarding these issues for newer AEDs. 13 The AAN guideline recommends 4 newer AEDs (oxcarbazepine, gabapentin, lamotrigine, and topiramate) as first-line drugs along with the older agents. Notable is that 3 of these AEDs (except for oxcarbazepine) are not approved in the United States for monotherapy of newly diagnosed patients. AAN states, The FDA does not accept such a finding as proof of efficacy, due to the possibility that two ineffective drugs might also exhibit no difference in effect when compared against one another. For the purpose of this parameter, we accepted the demonstration of equivalence between an established AED such as carbamazepine or phenytoin and a new drug as confirmation of effectiveness. 12 The FDA uses placebo-controlled clinical trials to evaluate the use of new AEDs as monotherapy in initial treatment of newly diagnosed epilepsy. 17 This type of trial can present an ethical dilemma to investigators who must randomize newly diagnosed patients to the placebo arm. In the recommendation for future research, AAN states There is no doubt that the ideal methodology for detecting drug effect in most cases is to use a placebo/control comparison. However, because trials in patients with newly diagnosed epilepsy must be performed, by definition, in the monotherapy condition, there are ethical concerns regarding a placebo or substandard control in this population. Therefore, comparative trials remain the preferred tactic. Clinicians favor these trial designs and these trials are not acceptable for registration purposes in the United States, as the FDA has required demonstration of superiority. Discussion is ongoing as to how to resolve this conflict between the needs of the clinician and the needs of regulatory bodies. 12 The United Kingdom and some countries in Europe accept active-control studies to approve monotherapy indication of new AEDs. 17 This may contribute to an explanation as to why AAN recommendations of newer AEDs differ from licensed indications in the United States. Beghi, in 2004, published a comparison of AAN and NICE guidelines. 18 His review included the use of newer AEDs in the treatment of epilepsy for both adults and children as well as in special populations (children and patients with learning disabilities and intellectual deficits, women of childbearing age, the elderly). Yet, the paper mainly focused on the place in therapy of newer agents according to these recent guidelines. He concluded that Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendation. And The U.K. guidelines are more conservative when compared to the U.S. guidelines. When evaluating specific recommendations from CPGs, it is crucial to understand the rationale for excluding CPGs whose recommendations are not considered. This permits a more transparent understanding of the potential for bias in the recommendations used in managed care. In this paper, we attempted to model this as a practice that should be employed when using CPG recommendations to inform drug policy decisions. Policymakers tend to utilize the findings or recommendations from research evidence sources that are clear in content, valid, and up-to-date. 19,20 The differences among CPGs recommendations present a dilemma to those trying to make drug policy decisions with an evidence-based approach and limit utilization of newer AEDs for maximum patient benefit. The variation among these CPGs might be a result of the process of guideline development. An evidence review to assess the treatment pattern of epilepsy management might be of interest, but it is beyond the scope of this paper. However, we could find no literature review regarding managed care in the U.S. practice. Since pharmacoeconomics and HrQoL are obvious Vol. 12, No. 1 January/February 2006 JMCP Journal of Managed Care Pharmacy 59

6 concerns of policymakers, future research should evaluate the cost-effectiveness and HrQoL of the initial AEDs treatment in adult patients with new-onset epilepsy in the United States to support drug policy decisions. Conclusion From our review of current CPGs for AEDs in the initial pharmacological management of epilepsy in adults published in the past 5 years, we found that the older AEDs, including carbamazepine, phenytoin, and valproic acid, still play an important role as first-line monotherapy for management of new-onset epilepsy in adults. Until cost-effectiveness data or quality-of-life studies show a convincing benefit for newer agents, they should remain second-line. DISCLOSURES No outside funding supported this study. The authors disclose no potential bias or conflict of interest relating to this article. Author Nalin Payakachat served as principal author of the study. Study concept and design were contributed by Payakachat and authors Kent H. Summers and John P. Barbuto. Data collection was the work of Payakachat; data interpretation was primarily the work of Payakachat, with input from Summers and Barbuto. Drafting of the manuscript and its revision was primarily the work of Payakachat, with input from Summers and Barbuto. REFERENCES 1. National Center for Chronic Disease Prevention and Health Promotion. Epilepsy: increasing awareness and improving care. Last reviewed September 3, Available at: Accessed February 23, Begley CE, Famulari M, Annegers JF, et al. The cost of epilepsy in the United States: an estimate from population-based clinical and survey data. Epilepsia. 2000;41(3): Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001; 42(120): World Health Organization. World report on knowledge for better health. Chapter 3: Strengthening health research systems. Geneva Available at: Accessed May 22, West E, Newton J. s [editorial]. BMJ. 1997;315: National Institute for Health and Clinical Excellence. Guideline development methods, Chapter 15: Updating guidelines and correcting errors. Available at: Accessed February 10, National Guideline Clearinghouse. Criteria for inclusion of clinical practice guidelines in NGC. Available at: inclusion.aspx. Accessed February 10, National Institute for Health and Clinical Excellence. Technology appraisal guidance 76: newer drugs for epilepsy in adults. Available at: Accessed July 5, National Collaborating Centre for Primary Care. The diagnosis and management of the epilepsies in adults and children in primary and secondary care. October Available at: epilepsies.pdf, and at CG020NICEguideline.pdf. Accessed July 5, Frost S, Crawford P, Mera S, Chappell B. National statement of good practice for the treatment and care of people who have epilepsy. Joint Epilepsy Council Available at: Accessed July 5, Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. A national clinical guideline 2003: Addendum released June Available at: and at Accessed July 5, French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62: Ross SD, Estok R, Chopra S, et al. Management of newly diagnosed patients with epilepsy: a systematic review of the literature. Evidence Report/Technology Assessment No.39 (Contract to MetaWorks, Inc.) AHRQ Publication No. 01-E038. Rockville, MD: Agency for Healthcare Research and Quality. September Available at: gov/books/bv.fcgi?rid=hstat1.chapter Accessed July 5, Facts & Comparisons Wolters Kluwer Health, Inc. Accessed November 29, National Institute for Health and Clinical Excellence. Technology assessment report: a rapid and systematic review of the clinical effectiveness, tolerability and cost effectiveness of newer drugs for epilepsy in adults. Available at: Accessed July 5, Kwan P, Brodie MJ. Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology. 2003;60(11 suppl 4):S2-S French JA, Schachter S. A workshop on antiepileptic drug monotherapy indications. Epilepsia. 2002;43(suppl 10):S3-S Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol. 2004;3: Bero LA. Jadad AR. How consumers and policymakers can use systematic reviews for decision making. Ann Intern Med. 1997;127: Innvaer S, Vist G, Trommald M, Oxman A. Health policy-makers perceptions of their use of evidence: a systematic review. J Health Serv Res Policy. 2002;7: Journal of Managed Care Pharmacy JMCP January/February 2006 Vol. 12, No. 1